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Mouse model of rare disease offers clues to aging and cancer development

20.08.2004


Scientists have developed the first mouse model of a rare disease in which people age rapidly and start developing cancers and other diseases associated with the elderly when they are only about 30 years old.



The advance, reported in the August issue of Nature Genetics, is already shedding light on a suspected strong link between aging and cancer by suggesting that a single cellular protein can play a role in both processes, according to researchers.

"Given that most cancer occurs in the elderly, aging is the biggest risk factor for developing cancer in humans," says the study’s lead author, Sandy Chang, M.D., Ph.D., assistant professor in the Department of Molecular Genetics at The University of Texas M. D. Anderson Cancer Center. "Now, with this animal model, we can look at the common pathways that unify aging and cancer development."


Working with Chang were researchers from Harvard Medical School, Brigham and Women’s Hospital in Boston, and the Massachusetts Institute of Technology.

Werner’s syndrome, which only strikes about one per million individuals worldwide, is the premier example of an adult-onset premature aging syndrome. Individuals with the disease have no symptoms for the first decade of life, but then begin to rapidly develop signs of aging, including thinning hair, wrinkling skin, cataracts, osteoporosis and diabetes, and they often die in their 40s of cancer or heart disease.

The root of the disease was found to be a failing gene that produces the protein WRN, known to help maintain the stability of the cell’s genome. Patients with Werner’s syndrome exhibit increased chromosomal aberrations, with pieces missing or fused onto other chromosomes, says Chang.

WRN also has been implicated in telomere maintenance. Telomeres are repeat sequences that cap the end of chromosomes and are necessary for chromosomal stability. They also are closely associated with the aging process - every time a cell divides, telomeres lose some of their length, and once telomeres become too short, the cell is programmed to stop dividing.

Because the features of accelerated aging in patients with Werner’s syndrome only begins to be seen after adolescence, the researchers hypothesized that telomere malfunction produced by a loss of WRN contributes to disease progression. In other words, when WRN is absent, telomeres shorten prematurely, leading to a cessation of cell growth that becomes apparent much earlier in life, says Chang.

"We believe that loss of WRN accelerates telomere shortening and promotes premature onset of aging phenotypes in mice," he says. "If that is true, then studying this mutation may give us a handle to understand what normally happens during the aging process."

But in order to test the idea that the symptoms of Werner’s syndrome require telomere shortening, the researchers had to create a mouse model of the disease. The first attempt by others to develop a mouse without WRN failed; the mice lived a long life. Scientists soon realized, however, that, in regard to telomeres, mice differ from those in humans in an important way. All cells in a mouse, they found, produce the enzyme telomerase that prevents telomeres from shortening, whereas only a few human tissue compartments typically "turn on" telomerase production. As a result, telomeres in mouse cells are much longer than in human cells, and mouse cells do not undergo the characteristic cessation of cell growth observed in human cells.

Knowing that, Chang and his colleagues bred mice without WRN to mice engineered not to produce telomerase. They then allowed the offspring to procreate through several generations in order to progressively shorten the telomeres. In the first two generations, the mice aged normally. In later generations, however, some of the mice - the ones with the shortest telomeres - began to exhibit the classic symptoms of Werner’s syndrome. They also developed certain non-epithelial cell cancers, including osteosarcomas, soft-tissues sarcomas and lymphoma. They also died at a much younger age than normal.

"The cancers these mice developed are fairly rare in the general human population, but are common in patients with Werner’s syndrome," says Chang.

Thus the mouse model shows that a deficit in WRN can lead to genomic instability that both accelerates aging and spurs cancer formation, according to the researchers.

Results of the study point to new avenues to explore, says Chang. Genomic instability also is the hallmark of cancers that develop in epithelial cells, which make up the majority of cancers in the general population. And this instability may also involve telomere length, he says.

For example, the master tumor suppressor gene p53 senses when a cell’s telomeres are too short and tells the cell to shut down. If p53 is dysfunctional, as it is in most cancers, the cell continues to divide. Telomeres that are too short increase genomic instability by promoting chromosomal fusions, a process which by itself is a risk factor for cancer development. But a "would be" cancer cell must also possess the ability to maintain their telomeres, otherwise they will die. Most human cancers keep their telomeres intact by turning on production of telomerase, thus ensuring that cells will remain immortal, dividing continually. "In fact, 90 percent of cancer cells use telomerase to keep the cells dividing," says Chang.

"The common denominator in aging and cancer appears in part to be the failure to maintain genomic stability, and how the p53 pathway senses this instability will ultimately determine whether a cell is programmed to stop dividing (aging) or progress to immortal growth (cancer)," he says. "Now we have a mouse model that will help us understand these links in detail."

Nancy Jensen | EurekAlert!
Further information:
http://www.mdanderson.org

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